BES: Cell-Level Responses Altered in GH-Normal Undersize Kids

Action Points

Explain to interested patients that a subset of children born small and with subsequent impaired growth have relatively normal levels of growth-related hormones, and this study suggests a reason.

Explain that combination treatment with IGF-1 and growth hormone for these children is not FDA approved. Explain, too, that this study was conducted on isolated cells in a laboratory, and the suggestion of benefit needs to be confirmed in clinical studies.

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

MANCHESTER, England -- Children born small who remain undersized despite normal growth hormone levels show an unusual pattern of responsiveness to insulin-like growth factor-1 (IGF-1) and growth hormone, a researcher said here.

Lab studies indicated that cell proliferation in response to IGF-1 was reduced and turnover was higher than normal in cells taken from children born small for their gestational age who fail to catch up, said Imogen Butcher, a doctoral candidate at the University of Manchester here.

In a poster presentation at the Society for Endocrinology meeting, also held here, Butcher said the findings were among the first clues as to why children may show marked growth deficits even though they produce growth-related hormones in normal quantities.

Many children are undersized at birth relative to the norm for their gestational age but, normally, "about 90% catch up" within a few years, Butcher said.

However, about 1,500 of those born annually in Great Britain remain small, more than two standard deviations less than the mean. For a 5-year-old, Butcher explained, that would mean being the size of a toddler.

In many of these children, no endocrine abnormality can be found.

As a dissertation project, Butcher has been conducting in vitro experiments with fibroblasts from these children and from those of age-matched growth-normal children to identify alterations in signaling associated with growth related hormones.

She found that, under basal and GH stimulated conditions, proliferation in SGA cells was comparable to controls, whereas response to IGF-1 over five days was significantly reduced to about two-thirds the rate of cells from normal children (P<0.001). However, when treated with a combination of GH and IGF-1 SGA, cells grew at a similar rate to controls.

Moreover, growth rates with the hormone combination in cells from undersized children were much greater than for either hormone alone.

Another difference between cells from the two groups of children was that apoptosis was higher in those from the undersized group. About 35% of cells from those children were undergoing apoptosis when placed in serum starving medium, compared with 30% of those from normal children (P<0.001).

Because apoptosis is an indicator of cell turnover, which occurs naturally, the finding indicated that this process is speeded up significantly in the growth-deficient group.

Butcher also found that treating these stressed cells with growth hormone or IGF-1 reduced apoptosis rates. But those rates still remained higher in the cells from undersized children compared with the control cells, she said.

Finally, Butcher examined the effects of the two hormones on intracellular signaling molecules, including Stat5b, Akt, and MAPK, known to mediate cellular responses to these growth factors.

Stat5b activation in response to growth hormone was diminished in the cells from undersized children, she discovered.

In contrast, IGF-1 activated Akt to a stronger degree in the cells from growth-deficient children relative to the normal cells.

Butcher said the findings did not entirely clear up the mystery of why growth remains impaired in these children. But the finding that co-treatment with IGF-1 and growth hormone "rescues" cell growth, at least in vitro, suggests that a similar approach might be helpful clinically.

Recombinant versions of both hormones are available commercially. Some forms of growth hormone (Genotropin, Norditropin) are FDA approved for children born small for gestational age whose growth does not catch up. IGF-1 (Increlex) is approved only for children deficient in IGF-1 or in those deficient in growth hormone who also have neutralizing antibodies against it.

The study was funded by Novo Nordisk.

Other than the research funding, Butcher reported no potential conflicts of interest.

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